N-(heteroaryl-methyl)-6,14-(endoethano or endoetheno)-7α-hydroxyalkyl-tetrahydro-nororipavines or-northebaines and salts thereof

ABSTRACT

Compounds of the formula ##SPC1## 
     Wherein 
     R 1  is hydrogen, methyl or acetyl, 
     R 2  is hydrogen or methyl, 
     R 3  is hydrogen, methyl, n-propyl, phenethyl or phenyl, 
     R 4  is hydrogen or methyl, 
     Z is --CH=CH-- or --CH 2  --CH 2  --, and 
     Y is oxygen or sulfur, 
     And non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as their salts are useful as analgesics and antitussives.

This invention relates to a novelN-(heteroaryl-methyl)-7α-hydroxyalkyl-6,14-(endoetheno orendoethano)-tetrahydro-nororipavines or -northebaines and non-toxic acidaddition salts thereof, as well as to various methods of preparing thesecompounds.

THE PRIOR ART

In J.A.C.S. 89, 3267 et seq. (1967), it is disclosed that compounds ofthe formula ##SPC2##

Wherein

R is allyl or cyclopropylmethyl,

R₁ is hydrogen or methyl,

R₂ and R₃ are hydrogen, alkyl, phenyl or aralkyl, and

Z is --CH=CH-- or --CH₂ --CH₂ --,

are very strong central analgesics and, in addition, exhibitmorphine-antagonistic properties.

THE INVENTION

More particularly, the present invention relates to a novel class ofN-(furylmethyl or thienylmethyl)-7α-hydroxy-alkyl-6,14-(endoethano orendoetheno)-tetrahydro-norori-pavines or -northebaines represented bythe formula ##SPC3##

Wherein

R₁ is hydrogen, methyl or acetyl,

R₂ is hydrogen or methyl,

R₃ is hydrogen, methyl, n-propyl, phenethyl or phenyl,

R₄ is hydrogen or methyl,

Z is --CH=CH-- or --CH₂ --CH₂ --, and

Y is oxygen or sulfur, and non-toxic, pharmacologically acceptable acidaddition salts thereof.

A preferred subgenus thereunder is constituted by those compounds of theformula I wherein R₁ is hydrogen, Y is oxygen, and the remainingvariables have the meanings previously defined.

The compounds may form isomers in the 7-position; "7α" means that thehydroxyalkyl substituent lies below the plane of the paper.

The compounds embraced by formula I may be prepared by the followingmethods.

Method A

By reacting an oripavine or thebaine derivative of the formula ##SPC4##

Wherein R₁, R₂, R₃ and Z have the same meanings as in formula I, with aheteroarylmethyl derivative of the formula ##SPC5##

Wherein

R₄ and Y have the meanings previously defined, and

X is halogen, preferably chlorine, bromine or iodine, alkyl--SO₂ --O--,aryl --SO₂ --O-- or trialkyl--ammonium, preferably (CH₃)₃ --N--.

The reaction of the compound of the formula II is performed with thecalculated amount, or a slight excess thereover, of the heteroarylmethylderivative of the formula III, optionally in the presence of anacid-binding agent. Examples of suitable acid-binding agents aretertiary amines, such as triethylamine or N,N-dicyclohexyl-ethylamine;alkali metal carbonates, such as sodium carbonate or potassiumcarbonate; alkali metal bicarbonates, preferably sodium bicarbonate; oralkali metal hydroxides or oxides. The reaction is advantageouslycarried out in an inert organic solvent medium, such as tetrahydrofuran,dioxane, methylene chloride, dimethylformamide, dimethylsulfoxide or amixture of two or more of these, preferably mixtures of tetrahydrofuranand dimethylformamide. The reaction temperature may vary within widelimits, but a temperature between 0°C. and the boiling point of theparticular solvent medium which is used is preferred. After completionof the reaction, the reaction product is isolated and crystallized byconventional methods.

Method B

By reacting a compound of the formula II with formaldehyde and a furanor thiophene of the formula ##SPC6##

wherein

Y and R₄ have the meanings defined above.

The reaction is carried out in weakly acid solution, especially in anacetic acid solution, and preferably in aqueous 50% acetic acid. Othersuitable solvents are water, lower alkanols, tetrahydrofuran, dioxane ormixtures of any two or more of these. The furan or thiophene of theformula IV is provided in the stoichiometric amount or in slight excessthereover, either dissolved or suspended in the solvent medium. Theformaldehyde may be provided in the form of paraformaldehyde orpreferably in the form of an aqueous solution in the calculated amountor in excess thereover. The reaction temperature may vary between -10°C.and the boiling point of the particular solvent medium which isemployed, but the preferred temperature is 25°C. After completion of thereaction, the reaction product is isolated and crystallized byconventional methods.

Method C

By reducing a compound of the formula ##SPC7##

wherein R₁, R₂, R₃, R₄, Z and Y have the meanings previously defined,or, for the preparation of a compound of the formula I wherein R₂ ishydrogen, by reducing a compound of the formula ##SPC8##

wherein R₁, R₃, R₄, Z and Y have the meanings previously defined.

Among the various suitable reduction methods, the reduction with acomplex hydride, in particular with lithium aluminum hydride, ispreferably used. Either the calculated quantity or, preferably, anexcess of the hydride, advantageously up to double the calculatedquantity, is provided. The reduction is advantageously performed in asuitable inert solvent or solvent mixture, such as ethers, butpreferably in tetrahydrofuran. The reaction temperature is variablewithin wide limits. Temperatures between 0°C. and the boiling point ofthe solvent or mixture of solvents are preferred.

If R₁ in formula V or Va is acetyl, the 0-acetyl group is split offsimultaneously with the reduction of the carbonyl groups, and in thiscase a compound of the formula I is obtained, wherein R₁ is hydrogen.The reaction product is isolated and crystallized by conventionalmethods.

Method D

For the preparation of a compound of the formula I wherein R₁ is methylor acetyl, by methylating or acetylating, respectively, a compound ofthe formula I wherein R₁ is hydrogen.

The methylation is effected in conventional manner, that is, by reactingthe starting compound with a conventional methylating agent, such asdiazomethane, a methyl ester of an inorganic acid, preferablydimethylsulfate, or a phenyl trimethylammonium compound.

The acetylation is effected with conventional acetylating agents, suchas an acetyl halide, preferably acetyl chloride, or acetic acidanhydride.

The methylation as well as the acetylation is advantageously carried outin the presence of an acidbinding agent, such as pyridine or anothertertiary amine, and in the presence of an inert solvent medium,preferably methylene chloride.

The starting compounds required for methods A to D are, to a largeextent, known compounds or may be prepared by known methods.

For instance, a compound of the formula II may be obtained by reacting acorresponding N-methyl derivative with cyanogen bromide to form theanalogous N-cyano-northebaine which is then hydrolized under alkalineconditions; depending upon the hydrolysis conditions, the nor-compoundof the formula II wherein R₁ is either methyl or hydrogen is obtained,that is, alkaline hydrolysis under more severe conditions simultaneouslysplits off the 0-methyl group.

A compound of the formula VI may be obtained by reacting a compound ofthe formula II with an acyl halide of the formula ##SPC9##

wherein R₄ and Y have the meanings previously defined and X' is halogen,preferably chlorine. Likewise, a compound of the formula Va may beobtained by reacting a Diels-Alder adduct of a nor-compound of theformula ##SPC10##

wherein R₁, R₂, R₃ and Z have the meanings previously defined, with anacyl halide of the formula VII.

The 6,14 - endoetheno derivatives of compounds of the formulas II, V, Vaand VII (where Z is --CH=CH--) may readily be converted into thecorresponding saturated 6,14-endethano-derivatives (where Z is --CH₂--CH₂ --) by catalytic hydrogenation.

The compounds embraced by formulas III, IV and VI are all knowncompounds, and many of them are readily available in commerce.

The compounds of the formula I are bases and therefore form acidaddition salts with inorganic or organic acids. Examples of non-toxic,pharmacologically acceptable acid addition salts are those formed withhydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid,sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionicacid, butyric acid, valeric acid, pivalic acid, caproic acid, oxalicacid, malonic acid, succinic acid, maleic acid, fumaric acid, lacticacid, tartaric acid, citric acid, malic acid, benzoic acid, phthalicacid, cinnamic acid, salicylic acid, ascorbic acid,8-chlorotheophylline, methanesulfonic acid, ethanephosphonic acid or thelike.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. Itshould be understood, however, that the invention is not limited solelyto the particular examples given below.

EXAMPLE 1N-Furfuryl-6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavineand its hydrochloride by method A

A mixture consisting of 3.69 gm (0.01 mol) of6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavine,1.26 gm (0.015 mol) of sodium bicarbonate, 1.28 gm (0.011 mol) offurfuryl chloride and 35 ml of a 2:1-mixture of tetrahydrofuran anddimethylformamide was refluxed for five hours, accompanied by stirring.Thereafter, the reaction solution was evaporated in vacuo, the residuewas shaken with a mixture of methylene chloride and water, and theorganic phase was separated, washed twice with water, dried over sodiumsulfate and evaporated. The residue, the free baseN-furfuryl-6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavine,was dissolved in 20 ml of absolute ethanol, the resulting solution wasacidified with 2 ml of 5N hydrochloric acid, the acidic solution wascarefully admixed with ether, and the precipitate formed thereby wascollected. 2.4 gm (49.3% of theory) of the hydrochloride of the formula##SPC11##

where Z is --CH=CH--, with a melting point of 224°-226°C. were obtained.

EXAMPLE 2

Using a procedure analogous to that described in Example 1, 46% oftheory ofN-furfuryl-6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-northebaine,m. p. 113°-116°C., was obtained from6,14-endetheno-7α-(hydroxy-methyl)-tetra-hydro-northebaine and furfurylchloride.

EXAMPLE 3

Using a procedure analogous to that described in Example 1,N-furfuryl-6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-nororipavineand 35% of theory of its hydrochloride, m. p. 212°-218°C., were obtainedfrom 6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-nororipavine andfurfuryl chloride.

EXAMPLE 4

Using a procedure analogous to that described in Example 1,N-(3'-furylmethyl)-6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-northebaineand 51% of theory of its hydrochloride, m. p. 254°-256°C., were obtainedfrom 6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-northebaine and3-chloromethyl-furan.

EXAMPLE 5

Using a procedure analogous to that described in Example 1,N-(3'-furylmethyl)-6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-nororipavineand 35% of theory of its hydrochloride, m. p. 222°-227°C., were obtainedfrom 6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-nororipavine and3-chloromethyl-furan.

EXAMPLE 6

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-northebaineand 46% of theory of its hydrochloride, m. p. 252°C.; were obtained from6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-northebaine and2-methyl-3-chloromethyl-furan.

EXAMPLE 7

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-nororipavineand 51% of theory of its hydrochloride, m. p. 220°-225°C., were obtainedfrom 6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-nororipavine and2-methyl-3-chloromethyl-furan.

EXAMPLE 8

Using a procedure analogous to that described in Example 1,N-(3'-furylmethyl)-6,14-endoetheno-7α(1"-hydroxyethyl)-tetrahydro-northebaineand 55% of theory of its hydrochloride, m. p. 237°-240°C., were obtainedfrom 6,14-endoetheno-7α-(1'-hydroxy-ethyl)-tetrahydro-northebaine and3-chloromethyl-furan.

EXAMPLE 9

Using a procedure analogous to that described in Example 1,N-(3'-furylmethyl)-6,14-endoetheno-7α-(1"-hydroxyethyl)-tetrahydro-nororipavineand 56.5% of theory of its hydrochloride, m. p. 250°-252°C., wereobtained from6,14-endoetheno-7α-(1'-hydroxy-ethyl)-tetrahydro-nororipavine and3-chloromethyl-furan.

EXAMPLE 10

Using a procedure analogous to that described in Example 1, 45% oftheory ofN-furfuryl-6,14-endoetheno-7α-(1'-hydroxy-ethyl)-tetrahydro-northebaine,m. p. 112°-114°C., was obtained from6,14-endoetheno-7α-(1'-hydroxy-methyl)-tetrahydro-northebaine andfurfuryl chloride.

EXAMPLE 11

Using a procedure analogous to that described in Example 1,N-furfuryl-6,14-endoetheno-7α-(1'-hydroxy-ethyl)-tetrahydro-nororipavineand 59.6% of theory of its hydrochloride, m. p. 242°-244°C., wereobtained from6,14-endoetheno-7α-(1'-hydrocy-ethyl)-tetrahydro-nororipavine andfurfuryl chloride.

EXAMPLE 12

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoetheno-7α-(1"-hydroxy-ethyl)-tetrahydro-northebaineand 60% of theory of its hydrochloride, m. p. 170°C., were obtained from6,14-endoetheno-7α-(1'-hydroxy-ethyl)-tetrahydro-northebaine and2-methyl-3-chloromethyl-furan.

EXAMPLE 13

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoetheno-7α-(1"-hydroxy-ethyl)-tetrahydro-nororipavineand 48% of theory of its hydrochloride, m. p. 180°C., were obtained from6,14-endoethano-7α-(1'-hydroxy-ethyl)-tetrahydro-nororipavine and2-methyl-3-chloromethyl-furan.

EXAMPLE 14

Using a procedure analogous to that described in Example 1, 52% oftheory ofN-(3'-furylmethyl)-6,14-endoethano-7α-(1"-hydroxy-ethyl)-tetrahydro-northebaine,m.p. 100°-102°C., of the formula ##SPC12##

where Z is --CH₂ --CH₂ --, were obtained from6,14-endoethano-7α-(1'-hydroxy-ethyl)-tetrahydro-northebaine and3-chloromethyl-furan.

EXAMPLE 15

Using a procedure analogous to that described in Example 1,N-(3'-furylmethyl)-6,14-endoethano-7α-(1"-hydroxyethyl)-tetrahydro-nororipavineand 46% of theory of its hydrochloride, m.p. 198°C., were obtained from6,14-endo-ethano-7α-(1'-hydroxy-ethyl)-tetrahydro-nororipavine and3-chloromethyl-furan.

EXAMPLE 16

Using a procedure analogous to that described in Example 1, 67% oftheory ofN-furfuryl-6,14-endoethano-7α-(1'-hydroxy-ethyl)-tetrahydro-northebaine,m.p. 127°-128°C., were obtained from6,14-endoethano-7α-(1'-hydroxy-ethyl)-tetrahydro-northebaine andfurfuryl chloride.

EXAMPLE 17

Using a procedure analogous to that described in Example 1,N-furfuryl-6,14-endoethano-7α-(1'-hydroxy-ethyl)-tetrahydro-nororipavineand 48% of theory of its hydrochloride, m.p. 250°-252°C., were obtainedfrom 6,14-endo-ethano-7α-(1'-hydroxy-ethyl)-tetrahydro-nororipavine andfurfuryl chloride.

EXAMPLE 18

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoethano-7α-(1"-hydroxy-ethyl)-tetrahydro-northebaineand 60% of theory of its hydrochloride, m.p. 175°C., were obtained from6,14-endoethano-7α-(1'-hydroxy-ethyl)-tetrahydro-northebaine and2-methyl-3-chloromethyl-furan.

EXAMPLE 19

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoethano-7α-(1"-hydroxy-ethyl)-tetrahydro-nororipavineand 40% of theory of its hydrochloride, m.p. 250°-255°C., were obtainedfrom 6,14-endoethano-7α-(1'-hydroxy-ethyl)-tetrahydro-nororipavine and2-methyl-3-chloromethyl-furan.

EXAMPLE 20

Using a procedure analogous to that described in Example 1, 81.5% oftheory ofN-(3'-thienylmethyl)-6,14-endoetheno-7α-(α-hydroxy-benzyl)-tetrahydro-northebaine,m.p. 215°-216°C., of the formula ##SPC13##

where Z is --CH=CH--, was obtained from6,14-endoetheno-7α-(α-hydroxy-benzyl)-tetrahydro-northebaine and3-chloromethylthiopene.

EXAMPLE 21

Using a procedure analogous to that described in Example 1, 78% oftheory ofN-thenyl-6,14-endoetheno-7α-(α-hydroxy-benzyl)-tetrahydro-northebaine,m.p. 205°-207°C, was obtained from6,14-endoetheno-7α-(α-hydroxy-benzyl)-tetrahydro-northebaine and thenylchloride.

EXAMPLE 22

Using a procedure analogous to that described in Example 1, 87.5% oftheory ofN-furfuryl-6,14-endoetheno-7α-(α-hydroxy-benzyl)-tetrahydro-northebaine,m.p. 179°-180°C, was obtained from6,14-endoetheno-7α-(α-hydroxy-benzyl)-tetrahydro-northebaine andfurfuryl chloride.

EXAMPLE 23

Using a procedure analogous to that described in Example 1,N-(3'-furylmethyl)-6,14-endoetheno-7α-(1'-hydroxy-1"-methyl-ethyl)-tetrahydro-northebaineand 46% of theory of its hydrochloride, m.p. 208°-212°C, were obtainedfrom6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-northebaineand 3-chloromethyl-furan.

EXAMPLE 24

Using a procedure analogous to that described in Example 1,N-(3'-furylmethyl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-nororipavineand 63% of theory of its hydrochloride, m.p. 215°-218°C, were obtainedfrom6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavineand 3-chloromethyl-furan.

EXAMPLE 25

Using a procedure analogous to that described in Example 1, 68% oftheory ofN-furfuryl-6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-northebaine,m.p. 108°-113°C, was obtained from6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-northebaineand furfuryl chloride.

EXAMPLE 26

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-northebaineand 58% of theory of its hydrochloride, m.p. 190°-192°C, were obtainedfrom6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-northebaineand 2-methyl-3-chloromethyl-furan.

EXAMPLE 27

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-nororipavineand 72.5% of theory of its hydrochloride, m.p. 215°-218°C, were obtainedfrom 6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavine and 2-methyl-3-chloromethyl-furan.

EXAMPLE 28

Using a procedure anlogous to that described in Example 1,N-(3'-thienylmethyl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-northebaineand 64% of theory of its hydrochloride, m.p. 190°-193°C, were obtainedfrom 6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-northebaine and3-chloromethyl-thiophene.

EXAMPLE 29

Using a procedure analogous to that described in Example 1,N-(3'-thienylmethyl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-nororipavineand 75.8% of theory of its hydrochloride, m.p. 190°-194°C, were obtainedfrom6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetra-hydro-nororipavineand 3-chloromethyl-thiophene.

EXAMPLE 30

Using a procedure analogous to that described in Example 1,N-thenyl-6,14-endoetheno-7α-(1'-hydroxy-1'-methylethyl)-tetrahydro-northebaineand 69.7% of theory of its hydrochloride, m.p. 182°-185°C, were obtainedfrom6,14-endo-etheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-northebaineand thenyl chloride.

EXAMPLE 31

Using a procedure analogous to that described in Example 1,N-thienyl-6,14-endoetheno-7α-(1'-hydroxy-1'-methylethyl)-tetrahydro-nororipavineand 55.8% of theory of its hydrochloride, m.p. 216°-220°C, were obtainedfrom6,14-endo-entheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavineand thenyl chloride.

EXAMPLE 32

Using a procedure analogous to that described in Example 1,N-(3'-furylmethyl)-6,14-endoethano-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-northebaineand 46% of theory of its hydrochloride, m.p. 220°-223°C, were obtainedfrom6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-northebaineand 3-chloromethyl-furan.

EXAMPLE 33

Using a procedure analogous to that described in Example 1,N-(3'-furylmethyl)-6,14-endoethano-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-nororipavineand 60.2% of theory of its hydrochloride, m.p. 215°-220°C, were obtainedfrom6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-noroipavineand 3-chloromethyl-furan.

EXAMPLE 34

Using a procedure analogous to that described in Example 1, 48.7% oftheory ofN-furfuryl-6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nothebaine,m.p. 130°-133°C, was obtained from6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-northebaineand furfuryl chloride.

EXAMPLE 35

Using a procedure analogous to that described in Example 1,N-furfuryl-6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavineand 63.2% of theory of its hydrochloride, m.p. 215°-220°C, were obtainedfrom6,14-endo-ethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavineand furfuryl chloride.

EXAMPLE 36

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoethano-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-northebaineand 73.4% of theory of its hydrochloride, m.p. 185°-187°C, were obtainedfrom6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-northebaineand 2-methyl-3-chloromethyl-furan.

EXAMPLE 37

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoethano-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-nororipavineand 44% of theory of its hydrochloride, m.p. 218°-222°C, were obtainedfrom6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavineand 2-methyl-3-chloromethyl-furan.

EXAMPLE 38

Using a procedure analogous to that described in Example 1,N-(3'-thienylmethyl)-6,14-endoethano-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-northebaineand 65.7% of theory of its hydrochloride, m.p. 188°-191°C, were obtainedfrom6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydronorthebaineand 3-chloromethyl-thiophene.

EXAMPLE 39

Using a procedure analogous to that described in Example 1,N-(3'-thienylmethyl)-6,14-endoethano-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-nororipavineand 55.8% of theory of its hydrochloride, m.p. 245°-248°C, were obtainedfrom6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavineand 3-chloromethyl-thiophene.

EXAMPLE 40

Using a procedure analogous to that described in Example 1, 62.2% oftheory ofN-thenyl-6,14-endothano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-northebaine,m.p. 145°-146°C, was obtained from6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-northebaineand thenyl chloride.

EXAMPLE 41

Using a procedure analogous to that described in Example 1,N-thenyl-6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavineand 48% of theory of its hydrochloride, m.p. 222°-224°C, were obtainedfrom6,14-endo-ethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavineand thenyl chloride.

EXAMPLE 42

Using a procedure analogous to that described in Example 1,N-(3'-furylmethyl)-6,14-endoethano-7α-(1"-hydroxy-1"-methyl-n-butyl)-tetrahydro-northebaineand 61% of theory of its hydrochloride, m.p. 190°-193°C, were obtainedfrom 6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-northebaineand 3-chloromethyl-furan.

EXAMPLE 43

Using a procedure analogous to that described in Example 1,N-(3'-furylmethyl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-n-butyl)-tetrahydro-noroipavineand 42% of theory of its hydrochloride, m.p. 200°-207°C, were obtainedfrom 6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydronororipavineand 3-chloromethyl-furan.

EXAMPLE 44

Using a procedure analogous to that described in Example 1,N-furfuryl-6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-northebaineand 75.8% of theory of its hydrochloride, m.p. 160°-165°C, were obtainedfrom6,14-endo-etheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-northebaineand furfuryl chloride.

EXAMPLE 45

Using a procedure analogous to that described in Example 1,N-furfuryl-6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-nororipavineand 54.5% of theory of its hydrochloride, m.p. 185°-187°C, were obtainedfrom6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-nororipavineand furfuryl chloride.

EXAMPLE 46

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-n-butyl)-tetrahydro-northebaineand 49.4% of theory of its hydrochloride, m.p. 196°-198°C, were obtainedfrom6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-northebaineand 2-methyl-3-chloromethyl-furan.

EXAMPLE 47

Using a procedure analogous to that described in Example 1, 47.5% oftheory ofN-(2'-methyl-3'-furylmethyl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-n-butyl)-tetrahydro-nororipavine,m.p. 220°-222°C, was obtained from6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-nororipavineand 2-methyl-3-chloromethyl-furan.

EXAMPLE 48

Using a procedure analogous to that described in Example 1, 59.8% oftheory ofN-(3'-thienylmethyl)-6,14-endo-enthano-7α-(1"-hydroxy-1"-methyl-n-butyl)-tetrahydro-northebaine,m.p. 172°-173°C, was obtained from6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-northebaineand 3-chloromethyl-thiophene.

EXAMPLE 49

Using a procedure analogous to that described in Example 1, 43.8% oftheory ofN-thenyl-6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-northebaine,m.p. 132°-133°C, was obtained from6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-northebaineand thenyl chloride.

EXAMPLE 50

Using a procedure analogous to that described in Example 1,N-furfuryl-6,14-endoethano-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-northebaineand 42.8% of theory of its hydrochloride, m.p. 154°-156°C, were obtainedfrom6,14-endoethano-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-northebaineand furfuryl chloride.

EXAMPLE 51

Using a procedure analogous to that described in Example 1,N-(3'-furylmethyl)-6,14-endoethano-7α-(1"-hydroxy-1"-methyl-n-butyl)-tetrahydro-northebaineand 74% of theory of its hydrochloride, m.p. 218°C, were obtained from6,14-endoethano-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-northebaineand 3-chloromethyl-furan.

EXAMPLE 52

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoethano-7α-(1"-hydroxy-1"-methyl-n-butyl)-tetrahydro-northebaineand 75.8% of theory of its hydrochloride, m.p. 172°-174°C, were obtainedfrom6,14-endoethano-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-northebaineand 2-methyl-3-chloromethyl-furan.

EXAMPLE 53

Using a procedure analogous to that described in Example 1, 66.7% oftheory ofN-(3'-furylmethyl)-6,14-endo-etheno-7α-(1"-hydroxy-1"-methyl-3"-phenyl-n-propyl)-tetra-hydro-northebaine,m.p. 170°-171°C, was obtained from6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-northebaineand 3-chloromethyl-furan.

EXAMPLE 54

Using a procedure analogous to that described in Example 1, 52% oftheory ofN-(3'-furylmethyl)-6,14-endo-etheno-7α-(1"-hydroxy-1"-methyl-3"-phenyl-n-propyl)-tetra-hydro-nororipavine,m.p. 245°-247°C, was obtained from6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-nororipavineand 3-chloromethyl-furan.

EXAMPLE 55

Using a procedure analogous to that described in Example 1,N-furfuryl-6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-northebaineand 57.7% of theory of its hydrochloride, m.p. 169°-171°C, were obtainedfrom6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-northebaineand furfuryl chloride.

EXAMPLE 56

Using a procedure analogous to that described in Example 1, 74% oftheory ofN-furfuryl-6,14-endoetheno-7α(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-nororipavine,m.p. 222°-224°C, was obtained from6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-nororipavineand furfuryl chloride.

EXAMPLE 57

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-3"-phenyl-n-propyl)-tetrahydro-northebaineand 56.7% of theory of its hydrochloride, m.p. 165°-169°C, were obtainedfrom6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-northebaineand 2-methyl-3-chloromethyl-furan.

EXAMPLE 58

Using a procedure analogous to that described in Example 1,N-(2'-methyl-3'-furylmethyl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-3"-phenyl-n-propyl)-tetrahydro-nororipavineand 40% of theory of its hydrochloride, m.p. 232°-234°C, were obtainedfrom6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-nororipavineand 2-methyl-3-chloromethyl-furan.

EXAMPLE 59

Using a procedure analogous to that described in Example 1, 84.5% oftheory ofN-(3'-thienylmethyl)-6,14-endo-etheno-7α-(1"-hydroxy-1"-methyl-3"-phenyl-n-propyl)-tetra-hydro-northebaine,m.p. 117°-119°C, was obtained from6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-northebaineand 3-chloromethyl-thiophene.

EXAMPLE 60

Using a procedure analogous to that described in Example 1, 77.5% oftheory ofN-thenyl-6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-northebaine,m.p. 139°-140°C, was obtained from6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-northebaineand thenyl chloride.

EXAMPLE 61N-(5'-Methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-nororipavineand its hydrochloride by method B

3.69 gm (0.01 mol) of6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavinewere dissolved in 10 ml of aqueous 50% acetic acid, and, while stirringthe resulting solution, it was admixed with 1.0 gm of aqueous 30%formaldehyde (0.01 mol formaldehyde). Subsequently, while stirring, 0.82gm (0.01 mol) of 2-methyl-furan was slowly added dropwise to themixture, and the resulting mixture was then stirred for 15 hours at roomtemperature. Thereafter, the reaction mixture was made alkaline withconcentrated ammonia while adding ice, then it was extracted withmethylene chloride, and the organic phase was washed several times withwater, dried over sodium sulfate and evaporated. The residue, the freebaseN-(5'-methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydronororipavine,was dissolved in ethanol, the solution was acidified with ethanolichydrochloric acid, and ether was added until the solution began to turncloudy. The precipitate formed thereby was collected, yielding 3.2 gm(62% of theory) of the hydrochloride which had a melting point of191°-195°C.

EXAMPLE 62N-(3'-Methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-nororipavineand its hydrochloride by method C

3.69 gm (0.01 mol) of6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavinewere suspended in 35 ml of methanol, the suspension was admixed with asolution of 2.5 gm of potassium carbonate in 4 ml of water, and then,while cooling the mixture, 1.74 gm (0.011 mol) of3-methyl-furan-2-carboxylic acid chloride were added dropwise over aperiod of 20 minutes, and the resulting mixture was stirred for threehours. Thereafter, the reaction mixture was evaporated in vacuo, theresidue was dissolved in methylene chloride, and the resulting solutionwas washed successively several times with water, dilute hydrochloricacid, dilute sodium bicarbonate solution and again with water. Theorganic phase was dried over sodium sulfate, evaporated in vacuo, theresidue was dissolved in 50 ml of absolute tetrahydrofuran, theresulting solution was added dropwise to a solution of 0.76 gm (0.02mol) of lithium aluminum hydride in 25 ml of tetrahydrofuran at 5° to10°C, and the mixture was stirred overnight at room temperature.Thereafter, the resulting suspension was carefully admixed with 1.5 mlof water while cooling on ice, then 75 ml of saturated aqueousdiammonium tartrate were added, and the mixture was allowed to stand forone hour. The tetrahydrofuran (upper) phase was separated andevaporated, the aqueous phase was extracted twice with methylenechloride, the residue of the tetrahydrofuran phase evaporation wasdissolved and the combined methylene chloride extracts, and theresulting solution was washed several times with water, dried oversodium sulfate and evaporated in vacuo. The residue, the free baseN-(3'-methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-nororipavine,was dissolved in ethanol, the solution was acidified with etherealhydrochloric acid, and the crystalline substance which separated out wascollected, yielding 2.2 gm (45% of theory) of the hydrochloride whichhad a melting point of 195°C.

EXAMPLE 63

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-ethyl)-tetrahydro-northebaineand 60.4% of theory of its hydrochloride, m.p. 165°-169°C, were obtainedfrom 6,14-endoetheno-7α-(1'-hydroxy-ethyl)-tetrahydro-northebained and3-methyl-furoyl chloride, and subsequent reduction of the intermediatewith lithium aluminum hydride.

EXAMPLE 64

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-ethyl)-tetrahydro-nororipavineand 77.6% of theory of its hydrochloride, m.p. 230°-232°C, were obtainedfrom 6,14-endoetheno-7α-(1'-hydroxy-ethyl)-tetrahydro-nororipavine and3-methyl-furoyl chloride, and subsequent reduction of the intermediatewith lithium aluminum hydride.

EXAMPLE 65

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoethano-7α-(1"-hydroxy-ethyl)-tetrahydro-northebaineand 64.4% of theory of its hydrochloride, m.p. 190°-192°C, were obtainedfrom 6,14-endoethano-7α-(1'-hydroxy-ethyl)-tetrahydro-northebaine and3-methyl-furoyl chloride, and subsequent reduction of the intermediatewith lithium aluminum hydride.

EXAMPLE 66

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoethano-7α-(1"-hydroxy-ethyl)-tetrahydro-nororipavineand 47.6% of theory of its hydrochloride, m.p. 230°-235°C, were obtainedfrom 6,14-endoethano-7α-(1'-hydroxy-ethyl)-tetrahydro-nororipavine and3-methyl-furoyl chloride, and subsequent reduction of the intermediatewith lithium aluminum hydride.

EXAMPLE 67

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-northebaineand 62.3% of theory of its hydrochloride, m.p. 170°-172°C, were obtainedfrom6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetra-hydro-northebaineand 3-methyl-furoyl chloride, and subsequent reduction of theintermediate with lithium aluminum hydride.

EXAMPLE 68

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoethano-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-northebaineand 58% of theory of its hydrochloride, m.p. 155°-157°C, were obtainedfrom6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl)-tetra-hydro-northebaineand 3-methyl-furoyl chloride, and subsequent reduction of theintermediate with lithium aluminum hydride.

EXAMPLE 69

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoethano-7α-(1"-hydroxy-1"-methyl-ethyl)-tetrahydro-nororipavineand 72.5% of theory of its hydrochloride, m.p. 210°-212°C, were obtainedfrom6,14-endoethano-7α-(1'-hydroxy-1'-methyl-ethyl))-tetra-hydro-nororipavineand 3-methyl-furoyl chloride, and subsequent reduction of theintermediate with lithium aluminum hydride.

EXAMPLE 70

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-n-butyl)-tetrahydro-northebaineand 71.2% of theory of its hydrochloride, m.p. 170°-172°C, were obtainedfrom6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-northebaineand 3-methyl-furoyl chloride, and subsequent reduction of theintermediate with lithium aluminum hydride.

EXAMPLE 71

Using a procedure analogous to that described in Example 62, 50.4% oftheory ofN-(3'-methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-n-butyl)-tetrahydro-nororipavine,m.p. 204°-206°C, was obtained from6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetrahydro-nororipavineand 3-methyl-furoyl chloride, and subsequent reduction of theintermediate with lithium aluminum hydride.

EXAMPLE 72

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoethano-7α-(1"-hydroxy-1"-methyl-n-butyl)-tetrahydro-northebaineand 56.8% of theory of its hydrochloride, m.p. 155°-159°C, were obtainedfrom6,14-endoethano-7α-(1'-hydroxy-1'-methyl-n-butyl)-tetra-hydro-northebaineand 3-methyl-furoyl chloride, and subsequent reduction of theintermediate with lithium aluminum hydride.

EXAMPLE 73

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-3"-phenyl-n-propyl)-tetrahydro-northebaineand 56.7% of theory of its hydrochloride, m.p. 211°C, were obtained from6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-northebaineand 3-methyl-furoyl chloride, and subsequent reduction of theintermediate with lithium aluminum hydride.

EXAMPLE 74

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-1"-methyl-3"-phenyl-n-propyl)-tetrahydro-nororipavineand 61% of theory of its hydrochloride, m.p. 247°-248°C, were obtainedfrom6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-3'-phenyl-n-propyl)-tetrahydro-nororipavineand 3-methyl-furoyl chloride, and subsequent reduction of theintermediate with lithium aluminum hydride.

EXAMPLE 75

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-methyl)-tetrahydro-northebaineand 33% of theory of its hydrochloride, m.p. 200°-202°C, were obtainedfrom 6,14-endoetheno-7α-(1'-hydroxy-methyl)-tetrahydro-northebaine and3-methyl-furoyl chloride, and subsequent reduction of the intermediatewith lithium aluminum hydride.

EXAMPLE 76

Using a procedure analogous to that described in Example 62,N-(3'-methyl-furfuryl)-6,14-endoetheno-7α-(1"-hydroxy-methyl)-tetrahydro-nororipavineand 34% of theory of its hydrochloride, m.p. 195°-199°C, were obtainedfrom 6,14-endoetheno-7α-(1'-hydroxy-methyl)-tetrahydro-nororipavine and3-methyl -furoyl chloride, and subsequent reduction of the intermediatewith lithium aluminum hydride.

EXAMPLE 77N-furfuryl-3-(O-acetyl)1-(O-acetyl)--endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavineby method D

A mixture consisting of 4.46 gm (0.01 mol) ofN-furfuryl-6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydro-nororipavine,10 ml of acetic acid anhydride and 0.82 gm (0.1 mol) of sodium acetatewas heated for one hour at 100°C. Thereafter, the reaction mixture wasallowed to cool, was then poured over 100 gm of ice, and after aninterval of five minutes the aqueous mixture was made distinctlyalkaline with aqueous 30% sodium hydroxide. The resulting suspension wasextracted with methylene chloride, and the organic extract solution waswashed several times with water, dried over sodium sulfate andevaporated, yielding 3 gm (62.5% of theory) of the compound of theformula ##SPC14##

where Z is --CH=CH--, which had a melting point of 122°-123°C(recrystallized from petroleum ether).

The compounds of the present invention, that is, those embraced byformula I and their non-toxic, pharmacologically acceptable acidaddition salts, have useful pharmacodynamic properties. Moreparticularly, the compounds of the instant invention exhibitnon-narcotic analgesic and antitussive activities in warm-bloodedanimals such as mice and rats.

All of the compounds of the present invention proved to be ineffectiveas analgesics in the Haffner test for analgesia [Deutsche MedizinischeWochenschrift 55, 731 (1929)] on mice and rats.

On the other hand, the compounds of this invention exhibit a distinct,dose-dependent analgesic activity in more sensitive phamacological testsfor analgesia, such as the hot-plate test [J. Pharmacol. Exp. Therap.80, 300 (1944)] or the writhing test [J. Pharmacol. Exp. Therap. 154,319 (1966)].

In accordance with presently prevailing teachings [Adv. Chem. Soc. 49,162-169 (1964)], inactivity in the Haffner test is indicative ofnon-narcotic properties, while activity in the hot-plate test and/orwrithing test proves analgesic properties.

For pharmaceutical purposes the compounds according to the presentinvention are administered to warm-blooded animals perorally, enterallyor parenterally as active ingredients in customary dosage unitcompositions, that is, compositions in dosage unit form consistingessentially of an inert pharmaceutical carrier and one effective dosageunit of the active ingredient, such as tablets, coated pills, capsules,wafers, powders, solutions, suspensions, emulsions, syrups,suppositories and the like. One effective oral analgesic and antitussivedosage unit of the compounds according to the present invention is from0.016 to 6.7 mgm/kg body weight, preferably 0.41 to 3.4 mgm/kg bodyweight.

The following examples illustrate a few pharmaceutical dosage unitcompositions comprising a compound of the present invention as an activeingredient and represent the best modes contemplated of putting theinvention into practical use. The parts are parts by weight unlessotherwise specified.

EXAMPLE 78 Tablets

The tablet composition is compounded from the following ingredients:

    N-Furfuryl-7α-(hydroxy-methyl)-6,14-                                    endoetheno-tetrahydro-northebaine                                                                     50.0     parts                                        Lactose                 95.0     "                                            Corn starch             45.0     "                                            Colloidal silicic acid  2.0      "                                            Soluble starch          5.0      "                                            Magnesium stearate      3.0      "                                            Total                   200.0    parts                                    

Preparation

The northebaine compound is intimately admixed with the lactose and thecorn starch, the mixture is moistened with an aqueous 10% solution ofthe soluble starch, the moist mass is forced through a 1 mm-mesh screen,the resulting granulate is dried at 40°C, the dry granulate is admixedwith the colloidal silicic acid, and the composition is compressed into200 mgm-tablets in a conventional tablet making machine. Each tabletcontains 50 mgm of the northebaine compounds and is an oral dosage unitcomposition with effective analgesic and antitussive actions.

EXAMPLE 79 Coated pills

The pill core composition is compounded from the following ingredients:

    N-Furfuryl-6,14-endoetheno-7α-(hydroxy-                                 methyl)-tetrahydro-nororipavine                                               hydrochloride            75.0    parts                                        Lactose                  100.0   "                                            Corn starch              65.0    "                                            Colloidal silicic acid   2.0     "                                            Soluble starch           5.0     "                                            Magnesium stearate       3.0     "                                            Total                    250.0   parts                                    

Preparation

The ingredients are compounded in the same manner as in Example 78, andthe composition is compressed into 250 mgm-pill cores which aresubsequently coated with a thin shell consisting essentially of amixture of sugar, talcum and gum arabic and finally polished withbeeswax. Each coated pill contains 75 mgm of the nororipavine compoundand is an oral dosage unit composition with effective analgesic andantitussive activities.

EXAMPLE 80 Suppositories

The suppository composition is compounded from the followingingredients:

    N-Furfuryl-6,14-endoetheno-7α-(1'-hydroxy-                              1'-methyl-ethyl)-tetrahydro-nororipavine                                      hydrochloride            50.0    parts                                        Lactose                  250.0   "                                            Suppository base (e.g. cocoa butter)                                                                   1400.0  "                                            Total                    1700.0  parts                                    

Preparation

The nororipavine compound is intimately admixed with the lactose, andthe mixture is blended with the aid of an immersion homogenizer into thesuppository base which had previously been melted and cooled to about40°C. 1700 mgm-portions of the composition are poured into cooledsuppository molds and allowed to harden therein. Each suppositorycontains 50 mgm of the nororipavine compound and is a rectal dosage unitcomposition with effective analgesic and antitussive actions.

EXAMPLE 81 Hypodermic solution

The solution is compounded from the following ingredients:

    N-(2'-Methyl-3'-furylmethyl)-6,14-                                            endoetheno-7α-(hydroxy-methyl)-                                         tetrahydro-nororipavine                                                                              75.0      parts                                        Socium chloride        5.0       "                                            Double-distilled water 2000.0ad  "                                                                             by vol.                                  

Preparation

The nororipavine compound and the sodium chloride are dissolved in thedouble-distilled water, the solution is filtered until free fromsuspended particles, and the filtrate is filled under aseptic conditionsinto 2 cc-ampules which are subsequently sterilized and sealed. Eachampule contains 75 mgm of the nororipavine compound, and its contentsare an injectable dosage unit composition with effective analgesic andantitussive actions.

EXAMPLE 82 Drop solution

The solution is compounded from the following ingredients:

    N-Furfuryl-6,14-endoetheno-7α-(1'-hydroxy                               1'-methyl-ethyl)-tetrahydro-nororipa-                                         vine hydrochloride        0.80   parts                                        Methyl p-hydroxy-benzoate 0.06   "                                            Propyl p-hydroxy-benzoate 0.04   "                                            Demineralized water   q.s.ad                                                                            100.0  "                                                                             by vol.                                  

Preparation

The nororipavine compound and the p-hydroxy-benzoates are dissolved inthe demineralized water, the solution is filtered, and the filtrate isfilled into 100 ml-bottles. 10 ml of the solution contain 80 mgm of thenororipavine compound and are an oral dosage unit composition witheffective analgesic and antitussive actions.

Analogous results are obtained when any one of the other compoundsembraced by formula I or a non-toxic acid addition salt thereof issubstituted for the particular northebaine compound in Examples 78through 82. Likewise, the amount of active ingredient in theseillustrative examples may be varied to achieve the dosage unit range setforth above, and the amounts and nature of the inert pharmaceuticalcarrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:
 1. A compound of the formula ##SPC15##wherein R₁ is hydrogen,methyl or acetyl, R₂ is hydrogen or methyl, R₃ is hydrogen, methyl,n-propyl, phenethyl or phenyl, R₄ is hydrogen or methyl, and Z is--CH=CH-- or --CH₂ --CH₂ --, or a non-toxic, pharmacologicallyacceptable acid addition salt thereof.
 2. A compound of claim 1, whichis of the formula ##SPC16##wherein R₂ is hydrogen or methyl, R₃ ishydrogen, methyl, n-propyl, phenethyl or phenyl, R₄ is hydrogen ormethyl, and Z is --CH=CH-- or --CH₂ --CH₂ --or a non-toxic,pharmacologically acceptable acid addition salt thereof.
 3. A compoundof claim 1, which isN-furfuryl-6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-northebaine ora non-toxic, pharmacologically acceptable acid addition salt thereof. 4.A compound of claim 1, which isN-furfuryl-6,14-endoetheno-7α-(hydroxy-methyl)-tetrahydro-nororipavineor a non-toxic, pharmacologically acceptable acid addition salt thereof.5. A compound of claim 1, which isN-furfuryl-6,14-endoetheno-7α-(1'-hydroxy-1'-methyl-ethyl)-tetrahydronororipavineor a non-toxic, pharmacologically acceptable acid addition salt thereof.6. A compound of claim 1, which isN-(2'-methyl-3'-furylmethyl)-6,14-endoetheno-7α-(hydroxy-methyl)-tetra-hydro-nororipavineor a non-toxic, pharmacologically acceptable acid addition salt thereof.